Project Summary/Abstract Perivascular adipose tissue (PVAT, the fat immediately adjacent to blood vessels) is a fat depot just beginning to be appreciated for the contributions it makes to vascular function and human health, normally viewed as being anticontractile and vasculoprotective. PVAT in the splanchnic vessels is the visceral fat that is particularly important; visceral fat is associated with the greatest risk of cardiovascular disease. We have made the novel discovery that PVAT possesses an adrenergic system, defined here as the ability to synthesize, release, take up and metabolize catecholamines. This PVAT may be directly innervated by the sympathetic nervous system (SNS), adding an unappreciated level of vascular control exerted by the SNS. The novel observation that the sympathomimetic tyramine causes PVAT-dependent contraction supports that this adrenergic system is functional. These experiments add a new dimension to the physiological importance of PVAT, which naturally lends itself to the study of obesity in which PVAT burdens are increased and the SNS is activated. We connect with every project of this PPG to investigate the overall hypothesis that mesenteric PVAT/visceral fat contains a functional, active adrenergic system. We will use two important models. First, the rodent model of high fat (HF) fed obesity is an ideal choice of obesity models because of the way that it reflects human obesity and the role of the SNS as a driver of the elevated blood pressure observed in most forms of obesity. From the HF model, we will use the superior mesenteric artery, superior mesenteric vein and small mesenteric arteries and veins (+/- PVAT) given that both circulations contribute to blood pressure determination and splanchnic function. Second, we use of PVAT of the human mesenteric vasculature (lean and obese). We use a suite of integrated techniques ? live cell imaging of NE transporter function, PVAT biochemistry, real time PCR, whole animal physiology, isometric contraction and pharmacology ? to examine three aims. Aim 1 tests the hypothesis that PVAT possesses the ability to synthesize, store, take up, functionally release and metabolize NE, and is innervated by the SNS (adrenergic systems); identifying mechanistic process is the goal. Aim 2 is devised to identify whether NE turnover is elevated in the PVAT of HF vs control such that PVAT NE content is reduced while circulating NE levels are elevated. Aim 3 tests the physiological contributions of splanchnic PVAT adrenergic systems. Collectively, this work provides powerful support for a novel mechanism by which PVAT modifies vascular tone and ultimately blood pressure: through a local and neuronal adrenergic system.